ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1919C>T (p.Pro640Leu) (rs267607875)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075425 SCV000592428 likely pathogenic Lynch syndrome 2015-09-25 criteria provided, single submitter clinical testing
Invitae RCV000821758 SCV000962527 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 640 of the MLH1 protein (p.Pro640Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Lynch syndrome (PMID: 21404117, 21642682, 18561205). ClinVar contains an entry for this variant (Variation ID: 89946). Experimental studies have shown that this missense change affects some aspects of MLH1 protein function, including protein-protein interactions and cellular protein expression or stability (PMID: 21404117). This variant disrupts the p.Pro640 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15365995, 22854115, 24278394), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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